Abstract 899: Remarkable anti-tumor response in a HCC transgenic mouse model treated with GNS561 in combination with anti-PD1

Abstract

Abstract Introduction:Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, leading to 75,000 deaths annually. Immunotherapeutic intervention has emerged as a novel effective treatment to delay the progression of aggressive tumors and suppress tumor recurrence and metastasis. However, few clinical immunotherapy trials have been conducted in HCC patients and there is an unmet need for novel therapeutic strategies. Combinations of conventional and novel treatments with immune-oncologic agents are now regarded as a therapy that can dramatically improve the outcome of patients with HCC.GNS561 is a lysosomotropic small molecule that was investigated in the context of antitumor activity alone or in combination with a PD-1 inhibitor using a transgenic immunocompetent mouse model (ASV-B). Materials and Methods: 40 ASV-B mice were treated with either the vehicle (p.o. water pH= 4, 5 days per week), GNS561 (p.o. 50 mg/kg/5 days per week), mouse anti-PD1 antibody (i.p. 10 mg/kg/twice a week [BIW]) or a combination of GNS561 and mouse anti-PD1 (p.o. 50 mg/kg/5 days per week and i.p. 10 mg/kg/BIW respectively) for 8 weeks. Tumor burden was evaluated by measuring the liver volume and blood flow velocity in the coeliac trunk by US/doppler 4 and 8 weeks (W8) after treatment start, the macronodules count and liver weight at sacrifice (W8). Intra and peritumoral CD8+ cells were counted. Results: All treatments were well tolerated. No significant response was observed with the anti-PD1 monotherapy compared with the vehicle. At W8, GNS561 alone or in combination with an anti-PD-1 showed a significant rapid and durable tumor response based on the macronodule count, decreased liver blood flow in the coeliac trunk, liver volume and weight (-59% and -77%; -18% and -31%; -36% and -37%; -37% and -52%, respectively). Based on preliminary mechanistic data, GNS561 alone or in combination showed an increase in the count of CD8+ cells penetrating the tumor site compared to the vehicle and the anti-PD1 alone, suggesting GNS561 may reinstore the anti-PD1 activity by facilitating CD8+ cells to reach the tumor site to exert their antitumoral activity. Conclusion: GNS561 alone or in combination with an anti-PD1 showed a significant antitumoral response. A combination of GNS561 with an anti-PD1 could then be of clinical interest in the treatment of hepatocelullar carcinoma. Citation Format: Madani Rachid, Annemilaï Tijeras-Raballand, Cindy Serdjebi, Sonia Brun, Christelle Ansaldi, Eric Raymond, Philippe Halfon. Remarkable anti-tumor response in a HCC transgenic mouse model treated with GNS561 in combination with anti-PD1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 899.